Background: The European Society for Clinical Nutrition and Metabolism (ESPEN) has recently published consensus-based criteria for the diagnosis of malnutrition; in subjects identified at nutritional risk the diagnosis is confirmed by either BMI <18.5 kg/m2 or weight loss in combination with low BMI or low FFMI. Concerns have been raised whether this definition correctly classifies malnutrition in patients with normal weight or overweight and concomitant weight loss. Therefore, the aim of this research is to assess the association between weight loss and one-year mortality in hospitalized patients, stratified by BMI and FFMI subgroups. Methods: This prospective study included 769 patients admitted to the VU University Medical Center. Critical weight loss (CWL) was defined as >5% weight loss in the previous month or >10% weight loss in the previous six months. The association between CWL and one-year mortality was analyzed with a priori stratification by BMI cut-off values (</≥20.0 kg/m2 for patients <70 years and </≥22.0 kg/m2 for patients ≥70 years) and FFMI cut-off values (derived from BIA measurements, </≥15 kg/m2 for females and </≥17 kg/m2 for males). Mortality risks were calculated (HR, 95% CI). Results: CWL occurred in 35% of patients and was associated with an increased one-year mortality rate vs. no-CWL (25% vs. 15%, p = 0.001), HR for mortality risk 1.76 (1.26-2.45)). CWL + low FFMI was associated with higher mortality risk (HR 1.95 (1.20-3.17), whereas CWL + normal FFMI was not (HR 1.37 (0.85-2.21)). Among patients with normal/high BMI, those with CWL had a significantly higher mortality risk compared to those without critical weight loss, however additionally adding FFMI to that model showed that a low FFMI was crucial in the observed association with mortality (CWL + normal BMI + low FFMI, HR 2.69 (1.29-5.65); CWL + normal BMI + normal FFMI, HR 1.38 (0.84-2.27)). Conclusion: - Patients with critical weight loss have a higher one-year mortality compared to patients with no critical weight loss. FFMI seems to play a crucial role in this association, as normal weight patients with normal FFMI had lower mortality rates than their counterparts with low FFMI.